P434: MYELODYSPLASIA-RELATED MUTATIONS IN THE NEW ELN CLASSIFICATION: DOES CLONAL SIZE PLAY A ROLE?
Authors: Christian Rausch, Maja Rothenberg-Thurley, Annika Dufour, Stephanie Schneider, Hanna Gittinger, Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard J. Woermann, Wolfgang Hiddemann, Jan Braess, Michael von Bergwelt-Baildon, Karsten Spiekermann, Tobias Herold, Klaus H. Metzeler
Journal: HemaSphere (2023)

Background: The 2022 update of the European LeukemiaNet risk stratification system for AML (ELN-2022) considers several myelodysplasia-associated mutations (MRmut) as defining adverse risk in the absence of favorable genotypes. We and others have previously found that outcomes of patients reclassified only due to MRmut are comparable to intermediate risk patients (Rausch et al, ASH 2022; Jentzsch et al, BCJ, 2022). However, others have proposed that considering the clonal size of the mutations could improve the prognostic power of MRmut. One approach (Loghavi et al, Ash 2022) proposes using a numeric VAF-cutoff determined individually for each gene using a best fit classifier (MRnum). Another approach (Mecklenbrauck et al., ASH 2022) sets the VAF-cutoff at 90% of the highest VAF of any concurrent mutation (MRrel). Both hope to weed out subclonal MRmut. Both approaches have not yet been validated in another cohort. Aims: We aim to elucidate whether considering clonal size of MRmut improve their utility as class-defining alterations within ELN-2022. Methods: We studied 1,138 newly diagnosed AML patients (median age 57 years; range, 18–86 years) who received cytarabine-based intensive induction chemotherapy in two subsequent multicenter phase III trials of the German AML Cooperative Group (AMLCG-1999, clinicaltrials.gov identifier NCT00266136, n = 857; and AMLCG-2008, NCT01382147, n = 259) between 1999 and 2012. Twenty subjects were excluded due to missing genetic data. No patient received FLT3 inhibitors or gemtuzumab ozogamicin during first-line treatment. Median follow-up for of survivors was 98 months. Those reclassified based on MRmut were substratified using the approaches mentioned above. Results: As reported previously, 79 of the 1118 patients in our cohort were reclassified based on a MRmut. Of those, 2 had three concurrent MRmut, 18 had two and the remaining 59 patients one. Median VAFs were: BCOR: 0.36 (range 0.03-0.91); EZH2: 0.55 (0.02-0.85); SF3B1: 0.4 (0.22-0.51); SRSF2: 0.39 (0.11-0.48); STAG2: 0.47 (0.05-0.95); U2AF1: 0.42 (0.20-0.51); ZRSR2: 0.85 (0.04-0.92). Using MRnum, 59 of the 79 patients who would be considered adverse risk solely based on the presence of >=1 MRmut irrespective of VAF were still considered adverse. Using MRrel, 44 were still considered adverse. 50 patients were classified concordantly, and there was discordance for 29 (22 only seen as adverse using MRnum and 7 only with MRrel). Using MRrel, SRSF2 was significantly less likely to remain class-defining (16/24 patients no longer adverse, p=0.01), while U2AF1 remained class-defining in all patients (11/11, p=0.0009). No such associations were detected using MRnum, which seems logical as the cutoffs were defined individually for each mutation. Using either approach, those with MRmut below the cutoff (MRnum: p=0.005; MRrel: p=0.01) as well as those above the cutoff (MRnum: p=0.02; MRrel: p=0.01) had significantly better OS than other ELN-2022 adverse-risk patients. A significant difference of MRmut patients from intermediate-risk patients was not detected for both those below (MRnum: p=0.45; MRrel: p=0.73) and above (MRnum: p=0.15; MRrel: p=0.43) the cutoffs (Figure 1).Summary/Conclusion: In this large cohort of fit AML patients, we could not confirm the utility of either approach claiming to increase the predictive power of MRmut by considering clone size through introduction of a VAF cutoff. Our data continue not to support the inclusion of these mutations as adverse risk-defining markers in the new ELN-2022 classification. Our work also underscores the importance of validating prognostic models in independent cohorts. Keywords: Acute myeloid leukemia, ELN, Myelodysplasia